Pharmacological interaction between benzodiazepines and voriconazole in patients with haematological malignancies

Abstract number: O22

Heinz W.J., Kloeser C., Kuhn A., Kahle K., Keller D., Einsele H., Klinker H.

Objective: Voriconazole is recommended as first line antifungal therapy for invasive aspergillosis and is often used in patients suffering from haematological malignancies. Metabolised by cytochrome P450 (mainly isoenzymes 2C9, 2C19 and 3A4), voriconazole is also a potent inducer and inhibitor of this important enzyme system. Otherwise, voriconazole metabolism may be influenced by different comedication. Thus, drug-drug interactions are frequent in patients on voriconazole and may lead to treatment failure in case of enzyme induction or increased side effects in case of enzyme inhibition.

Especially, patients of older age and/or those undergoing chemotherapy receive sedatives also interacting with cytochrome P450. In the present study we investigated the impact of this often unintended combination on voriconazole pharmacokinetic.

Methods: Serum samples from hospitalised patients receiving voriconazole have been collected routinely since 2005. Comedication and patient characteristics were recorded. Trough levels of serum concentrations were determined by a high performance liquid chromatographic method (HPLC). Statistic analyses were performed by t-test.

Results: 259 voriconazole concentrations from 91 patients were determined including 17 samples from 14 patients receiving temazepam (group I), 20 samples from 9 patients with lorazepam (group II) and 222 samples from 68 patients without benzodiazepines (group III). Mean voriconazole concentration was 726 ng/ml in group I (p for I versus III: 0.0167), 1153 ng/ml in group II (p for II versus III: 0.17), and 1701 ng/ml in group III, the median levels were 302 ng/ml, 764 ng/ml and1159 ng/ml, respectively. Comparing all samples with (n = 35) and without comedication of benzodiazepines, mean voriconazole levels were 1007 ng/ml and 1579 ng/ml with a statistical power of p = 0.0123.

Conclusion: Benzodiazepines have a significant influence on the serum concentration of voriconazole. This pharmacological interaction should be taken into account during antifungal therapy. Therapeutic drug monitoring of voriconazole is helpful to identify patients who are at risk for treatment failure or increased side effects.